It is known that the slow reacting substance of anaphylaxis (SRS-A) is a mediator which is involved in allergic bronchiospasm (asthma) in man. It has been established that SRS-A is produced in the body by metabolism of arachidonic acid (C20:4.omega.6).
The alternate designations for fatty acids used throughout the present specification, such as C20:4.omega.6, refer to the total number of carbon atoms in the chain, before the colon; the number of unsaturated bonds, after the colon; and the number of carbon atoms from the end opposite the carboxylic acid at which the first unsaturation appears, following the omega. Members of a given omega series of fatty acids, e.g. .omega.3 can usually be converted to acids of differing lengths and total number of unsaturations by normal bodily enzymes, but it is generally impossible to change a compound from one omega series to another, e.g. .omega.3 to .omega.6. This is because bodily enzymes generally cause changes of length and unsaturation to occur starting from the carboxylic acid end of the chain.
Arachidonic acid is stored in the membranes of the body as part of phospholipids. The arachidonic acid is released from such phospholipids by the action of a phospholipase. The production of the phospholipase which causes release of arachidonic acid may be triggered by any of a variety of mechanisms, including physical irritation and hypersensitivity. Once the arachidonic acid is released into the circulation, it may be oxidized by two different pathways. It is either metabolized by cyclo-oxygenase to produce prostaglandins, or by lipoxygenase to generate hydroperoxy derivatives which may be further metabolized to leucotrienes and SRS-A.
It has previously been theorized that SRS-A production can be inhibited by the inhibition of one or more of the enzymes required for its formation. For example, it is known that corticosteroids act to inhibit the phospholipase stage. Thus, the release of arachidonic acid is inhibited causing the inhibition of the production of all of the metabolites of arachidonic acid, including the prostaglandins. Thus, corticosteroids have been used as anti-inflammatories (inhibition of prostaglandins) as well as anti-asthmatics (inhibition of SRS-A). Unfortunately, however, corticosteroids have severe side effects.
Aspirin-like compounds and indomethacin inhibit only the cyclo-oxygenase pathway of arachidonic acid metabolism. Thus, these compounds can do nothing toward the treatment of asthmatic conditions and, in fact, giving aspirin to an asthmatic may provoke an attack because it forces SRS-A production by inhibiting the cyclo-oxygenase pathway of arachidonic acid.
Compounds which inhibit both the cyclo-oxygenase and lipoxygenase pathways for arachidonic acid metabolism can be expected to reduce SRS-A formation, but are also expected to have undesirable side effects due to the inhibition of the cyclo-oxygenase pathway, as for example, the formation of stomach ulcers. Furthermore, substantially non-toxic natural substances which inhibit both cyclo-oxygenase and lipoxygenase are not known.
Another reason why it is undesirable for an anti-asthmatic drug to also inhibit cyclo-oxygenase is because cyclo-oxygenase is involved in the metabolism of PGE.sub.1 from dihomo-gamma-linolenic acid (C20:6.omega.6), which is an important and desirable prostaglandin. PGE.sub.1 interferes with the biosynthesis of cholesterol and endothelial cell proliferation.
Furthermore, there are a variety of lipoxygenases which oxidize various points of the arachidonic acid molecule. The lipoxygenase which catalyzes the production of SRS-A is the 5-lipoxygenase, which oxidizes the double bond of the 5-carbon atom of arachidonic acid. It is thus desirable to specifically inhibit 5-lipoxygenase, thus avoiding inhibition of other enzymes which produce products which are not necessarily undesirable.
The best drug for reduction of SRS-A and thereby for treatment of asthmatic attacks and bronchial spasms, would be a specific 5-lipoxygenase inhibitor which does not inhibit cyclo-oxygenase or other lipoxygenases. Preferably, such a compound should be naturally occurring, so as to be as nontoxic as possible.